Onvansertib

Cardiff Oncology reported that adding a high dose of its experimental candidate onvansertib to standard treatments shrank tumors in a mid-stage study of patients with KRAS-mutated colorectal cancer. The Phase 2 study shows that there was a 19-percentage point difference in the confirmed overall response rate between patients in the experimental arm and those who received standard treatments alone. The company’s lead asset blocks a key cell growth protein called PLK1. Cardiff is studying onvansertib across the nearly half of all metastatic colorectal cancers that harbor KRAS mutations. Unlike a KRAS inhibitor such as Amgen’s Lumakras, which can only address a specific KRAS mutation, Cardiff hopes its drug can be used to treat the range of KRAS-mutated colorectal cancers. In the trial, 110 patients received chemotherapy and bevacizumab alone or alongside a 20 mg or 30 mg dose of Cardiff’s drug as a first-line treatment. Cardiff reported that 49% of patients who received the high dose of onvansertib had a confirmed response, compared to 30% of those who received placebo. Among patients who received the 20 mg dose, 42% responded to treatment. However, Cardiff’s stock $CRDF fell around 25% at market open Wednesday. It had reported an earlier cut of data in December, showing a 31-point difference between the response rate of the high-dose arm and the placebo group — but in fewer patients. Jefferies analyst Maury Raycroft called Tuesday’s readout “encouraging” in a note to investors, but noted more data were needed around the durability of responses. Cardiff CEO Mark Erlander told Endpoints News that pending discussions with the FDA, the company expects to move the 30 mg dose forward into late-stage studies. Cardiff is planning to give another update on the mid-stage study early next year, and then it hopes to start a pivotal study next year as well. Erlander said a key feature of Cardiff’s drug is that it targets PLK1 very specifically. Previous iterations of PLK inhibitors, such as Boehringer Ingelheim’s volasertib, were not as specific and therefore led to substantial toxicities. In the updated data shared Tuesday, Cardiff reported that the drug combination was “well-tolerated and there were no major or unexpected toxicities observed,” though some patients experienced neutropenia associated with onvansertib. Cardiff chief medical officer Roger Sidhu told Endpoints that rates of adverse events were comparable across the control and treatment arms. Outside of Cardiff, few are studying drugs aimed at PLK1. Raycroft wrote in June that Cardiff is working in an arena that “has seen little innovation and lacks major late-stage competitors,” as most others are targeting narrow mutation subpopulations. Editor’s note: Cardiff’s stock move was updated.

Cardiff Oncology's stock plunged nearly 28% on Wednesday despite the company touting "positive" results from the latest readout of its Phase II trial testing PLK1 inhibitor onvansertib in first-line RAS-mutated metastatic colorectal cancer (mCRC).Participants in the CRDF-004 study received standard treatment (FOLFIRI or FOLFOX, plus bevacizumab) and were randomised to one of six groups, including onvansertib at 20 mg or 30 mg, both on top of standard care, or standard care alone. The latest readout is based on 110 patients with a July 8 data cutoff, up from Cardiff's initial December data release that showed promising signals in 30 patients. In that earlier analysis, the high-dose onvansertib arm had demonstrated a 64% objective response rate (ORR), nearly double the 33% seen with standard therapy.Narrowing gapHowever, in the expanded dataset, the response gap narrowed: the 30-mg group had a 59% ORR, compared to 43% in the control arm. Confirmed responses were 49% and 30%, respectively.The shrinking margin may have disappointed investors. Still, analysts at Jefferies recently noted that a 20% response delta would generally be considered encouraging, though they cautioned that meaningful efficacy data, including an early look at durability signals, likely wouldn't emerge until later in the year."The totality of the data…strengthens the initial findings from our December 2024 data release in a significantly larger patient population, compares favourably to previous practice-changing Phase III trials," said Roger Sidhu, chief medical officer. "Furthermore, early PFS (progression-free survival) data shows a trend favouring the 30-mg dose of onvansertib vs. control."CEO Mark Erlander said the data "positions us to engage in discussions with the FDA as we advance toward our registrational CRDF-005 trial."Failed vitiligo studyVYNE Therapeutics suffered a steeper drop, with shares tumbling more than 71% on Wednesday after the company said its experimental vitiligo treatment failed to meet primary and key secondary endpoints in a Phase IIb trial. CEO David Domzalski said VYNE would seek an external partner to continue development of repibresib gel, a pan-bromodomain BET inhibitor designed to be locally administered as a 'soft' drug to address diseases involving inflammatory cell signaling pathways, while providing low systemic exposure.The trial evaluated 177 patients with nonsegmental vitiligo, testing three concentrations of repibresib gel against vehicle. The study failed to achieve its primary endpoint – the proportion of patients showing at least 50% improvement on Facial Vitiligo Area Scoring Index (F-VASI50) at 24 weeks – with response rates ranging from 16.3% to 19.5% for the active doses compared to 23.4% for placebo. The trial also missed a key secondary endpoint of F-VASI75.However, the highest 3% dose showed a nominally statistically significant reduction in F-VASI scores from baseline, with a 43.6% improvement versus 25.6% for vehicle.Domzalski said the results "were impacted by an unexpectedly high treatment effect in the vehicle arm and a high discontinuation rate in the active arms." Despite the setback, he added, "We intend to seek a development and commercialization partner for repibresib and we will provide an update on our plans, including those for our oral BET inhibitor VYN202, in the coming weeks."In April, the FDA placed a clinical hold on the company's Phase Ib trial of VYN202 after a non-clinical toxicology study in dogs revealed signs of testicular toxicity, but recently lifted the hold for female patients at some lower doses.Alzheimer's biomarkersMeanwhile NewAmsterdam Pharma may have offered a bit of a bright spot amid the gloom. The company said its experimental cholesterol treatment obicetrapib demonstrated statistically significant reductions in key Alzheimer's disease biomarkers in a subset analysis of patients at highest risk for the neurodegenerative condition. Detailed findings from the Phase III BROADWAY trial were shared at the Alzheimer's Association International Conference (AAIC), building on preliminary results disclosed in June that suggested the CETP inhibitor could slow the accumulation of plasma p-tau217.The study was originally designed to evaluate obicetrapib's ability to lower LDL cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia. In December, the company reported that the drug achieved a 33% reduction in LDL-C, meeting the primary endpoint. However, a prespecified analysis of 1515 patients whose ApoE status could be determined revealed possible neurological benefits as well, including among the 367 carriers of the ApoE4 gene variant.In patients carrying two copies of the ApoE4 gene, obicetrapib reduced p-tau217 levels by 20.5% (p=0.01) over 12 months compared to placebo. Additional reductions observed in other neurodegeneration biomarkers including a 17.3% (p=0.02) decrease in neurofilament light chain and a nearly 13.7% (p=0.06) reduction in p-tau181."This is especially important in ApoE4 gene carriers – a group that represents over a quarter of the population and faces a heightened risk for this disease," said CEO Michael Davidson. "Combined with its LDL-C lowering benefits observed in multiple clinical trials, obicetrapib may offer a unique opportunity to reduce both neurodegenerative and heart disease risks."The company says it plans to discuss these findings with regulatory authorities to determine potential development pathways for a "novel, upstream approach" for Alzheimer's prevention.